This invention relates to phosphonated derivatives of macrolides. These compounds are useful as immunosuppressive agents.
The compounds of this invention are useful in preventing or treating graft rejection following skin and organ transplant surgery and in preventing or treating autoimmune diseases such as rheumatoid arthritis and psoriasis. They are also useful in preventing or treating infectious diseases caused by fungi.
Graft or organ transplant rejection following transplant surgery is a common occurrence which arises when foreign antigens are recognized by the host's immune response system. The host's immune response system, in an effort to protect itself from the foreign tissue, then releases a cellular and humoral arsenal, resulting in complications which often end in rejection of said tissue.
The occurrence of immunoregulatory irregularities in autoimmune and chronic inflammatory diseases is well known. Treatments which target the immune response system often result in a complete shutdown of the system, leading to a lowering of the body's ability to combat infection. This can be as dangerous as the original condition which led to the shutdown. Currently, the leading medicinal agent for the prevention or treatment of graft rejection is cyclosporin A, approved by the United States Food and Drug Administration in 1983. Cyclosporin can cause kidney failure, liver damage and ulcers; which in many cases can be very severe. Safer drugs that are more selective in their ability to affect the immune response system and which have fewer side effects are constantly being pursued.
U.S. Pat. No. 4,894,366, which issued on Jan. 16, 1990, describes the macrolides FK-506 and FK-520, inter alia, as immunosuppressants which are useful in the treatment of "resistance to transplantation," autoimmune diseases and infectious diseases.